The broad aim of this proposal is to test the hypothesis that drugs such as beta-blockers can be administered in a programmable fashion via electrically-assisted transdermal delivery, and that their irritation potential can be controlled by a liposomal formulation. Specifically, this project investigates the in vitro delivery of five beta-blockers, propranolol, oxprenolol, timolol, metoprolol, and sotalol across freshly excised hairless rat skin and uses the data to follow up with its in vivo delivery using hairless rats. This delivery system can be used for prophylaxis of migraine and control of hypertension in a programmed fashion or development of a closed loop self-regulated delivery system. In vitro studies will involve development of electrical parameters for iontophoresis alone (e.g., current density) or in combination with electroporation (e.g., pulse voltage, duration, and number of pulses) for delivery of therapeutically relevant concentrations, modulation of delivery, and minimizing skin depot. Beta-blockers will be delivered under anode using silver/silver chloride electrodes and analyzed by stereoselective HPLC assay. A constant current power supply will be used for iontophoresis and an exponential decay pulser will be used for electroporation. The recovery of skin impedance will be monitored for all protocols using an oscilloscope. Based on the best protocol, liposomal formulations will be substituted for solution formulations for limited in vitro studies. The best solution and liposomal formulation will then be taken to in vivo studies, where plasma drug levels will be analyzed and skin irritation will be assessed, using appropriate controls. Model dependent and independent pharmacokinetic parameters will be determined. Separate in vitro experiments with human skin will be used to fit a model for a mechanistic understanding of permeation pathways during electroporation.